Date of Award

1-1-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry

First Advisor

Samantha Meenach

Abstract

Drug delivery research focuses on overcoming challenges in patient treatment. Most therapeutics are delivered systemically through oral or intravenous routes. However, these administration methods are often inefficient due to therapeutic hydrophobicity, poor bioavailability, and liver metabolic clearance, necessitating frequent dosing. When treatment plans require frequent dosing, patients experience significant fluctuations in therapeutic concentration in the bloodstream, which can increase adverse side effects. These factors contribute to low patient compliance. Therefore, the core focus of drug delivery research is to develop new administration routes for therapeutics. Drug delivery systems (DDS) that can target therapeutics to a localized region offer advantages over traditional systemic drug delivery. Localized drug delivery enables therapeutics to be administered directly to the target site, thereby avoiding first-pass metabolism in the liver and providing rapid relief to enhance patient treatment.

Additionally, DDS can utilize polymers to regulate the release of therapeutics. Controlled drug release from these platforms improves treatment options for patients through regulating the release of therapeutics to maintain a constant concentration in the bloodstream, which reduces side effects. Additionally, controlled drug release eliminates the need for regular dosing. Common polymeric DDS for controlled release includes nanoparticles and electrospun fibers. Nanoparticles have favorable characteristics for drug delivery, including: a large surface area to volume ratio, high drug loading, improved therapeutic stability in harmful environments, potential surface functionality, and are readily internalized in the cell. The drug delivery capabilities of nanoparticles are desirable for a wide range of applications. Pulmonary drug delivery is of particular focus because of the favorable physiological conditions of the lungs. Lungs have a large surface area and low enzymatic activity to inhibit drug release. Ideally, localized delivery to the lung would utilize powder aerosol drug delivery. However, nanoparticles do not have favorable aerosol properties. Nanoparticles are too light and will not deposit in the lungs using aerosol drug delivery. Microparticles exhibit favorable aerosolized drug delivery to the deep regions of the lungs, but they are not ideal for internalization into cells. Therefore, the drug delivery capabilities of nanoparticles can be combined with the aerosol properties of microparticles in nanocomposite microparticles (nCmP).

Electrospun fibers can also be modified to provide favorable release for localized drug delivery through the formulation of a polymer scaffold. The scaffold has favorable interactions with cells due to its large surface area and high porosity, which enables the release of therapeutics based on the degradation profile of the polymer. As a result, modifications to the polymer composition can be utilized to provide a wide range of drug release profiles. The polymer composition can be modified by blending polymers to create a single fiber or core/shell electrospun fibers. Given the potential benefits of polymeric DDS, there is a wide range of applications for improving treatment options.

This dissertation aimed to (1) develop quercetin-loaded nanocomposite microparticles to improve the treatment of chronic inflammatory pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), (2) develop acetalated dextran/polycaprolactone (Ac-Dex/PCL) electrospun fibers to provide temporal drug release, (3) improve adjuvant treatments of hormone receptor positive (HR+) breast cancer through the creation of anastrozole (ANZ) hydroxypropyl-beta-cyclodextrin (h-β-CD) inclusion complexes (ANZ-CD) loaded into core/shell electrospun fibers.

Quercetin-loaded nCmP (Que-nCmP) were used as an antioxidant to treat inflammatory pulmonary disease. Quercetin-loaded nanoparticles (Que-NP) were formulated into nCmP via spray drying. Que-NP were successfully loaded with quercetin and had favorable diameters, poly dispersity index, and surface charge for drug delivery before and after redispersion from nCmP. Solid state characterization also indicated that Que-nCmP were amorphous, eliminating any crystalline peaks in raw quercetin, increasing the therapeutics' bioavailability. Que-nCmP also had favorable aerosolized properties as the majority of the particles had diameters ideal for aerosolized delivery to the deep regions of the lungs. In vitro studies of Que-NP indicate the ability of Que-nCmP to release quercetin. Que-nCmP also maintain their antioxidant properties after the synthesis, as there was no statistically significant difference compared to raw quercetin. Therefore, Que-nCmP have the potential to improve the treatment of chronic inflammatory pulmonary disease through aerosolized drug delivery.

Ac-Dex/PCL electrospun fiber formulations were formulated to evaluate the influence of different polymer ratios on encapsulated curcumin (CUR) release. The electrospun fibers synthesized had favorable diameters and pore sizes to release CUR. Additionally, the electrospinning process transitioned CUR from the crystalline to the amorphous state, increasing the bioavailability. Ac-Dex and PCL are biodegradable polymers, but have vastly different release profiles. In vitro release studies for Ac-Dex/PCL fiber formulations indicated the release of encapsulated CUR exhibited longer temporal release with increasing percentages of Ac-Dex. High amounts of PCL result in a shorter temporal release profile for encapsulated CUR. The hydrophobicity of the polymer was evaluated to determine the impact on the release profiles. Fibers with a high percentage of Ac-Dex were more hydrophobic than fibers with a high percentage of PCL. This indicates that the hydrophobicity of the Ac-Dex fiber formulation influenced the release profiles. Therefore, using different ratios of Ac-Dex and PCL can provide release over various time frames. This is particularly interesting in treatments that benefit from combined or spatiotemporal drug delivery.

ANZ-CD inclusion complexes were loaded into core/shell fibers to provide sustained drug release for the treatment of HR+ breast cancer. ANZ is a common endocrine treatment prescribed to patients after mastectomies to prevent recurrence. However, ANZ is poorly water soluble, has low bioavailability, and has harmful side effects. Therefore, treatment could benefit from improved solubility of ANZ through complexation with h-β-CD and encapsulation in a DDS for localized sustained drug delivery. ANZ-CD inclusion complexes were successfully complexed, shielding ANZ within the hydrophobic cavity of h-β-CD, increasing its solubility in aqueous solutions. To provide sustained release of ANZ from the inclusion complex, the complex was loaded into core/shell fibers consisting of polyvinyl alcohol (PVA) in the core and PCL in the shell. The release of ANZ from the inclusion complex was compared to ANZ loaded directly in the core or shell of the fiber. ANZ-CD provided a better sustained release, indicating the potential for h-β-CD inclusion complexes to provide additional variation to the release profiles of therapeutics encapsulated in electrospun fibers.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Download

Available for download on Wednesday, May 27, 2026

Share

COinS